# Molecular basis of effector protein export in the malaria parasite Plasmodium falciparum

> **NIH NIH DP5** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $405,000

## Abstract

Project Summary
Malaria is a devastating parasitic disease that affects more than 200 million people annually, resulting in nearly
500,000 deaths each year. As of 2018, the World Health Organization estimates that 3.8 billion people, roughly
half the world's population, are at risk of contracting malaria, and the rise of drug-resistant parasites has created
a desperate need for new anti-malarial drugs. While most intracellular pathogens export a limited repertoire of
effector proteins to co-opt existing host-cell metabolic machineries, the malaria-causing parasite Plasmodium
falciparum exports more than 10% of its proteome into its host, the human red blood cell, during the blood stages
of its life cycle. The hundreds of proteins in the P. falciparum exportome extensively remodel host erythrocytes,
creating the infrastructure needed to import nutrients, export waste, and evade the host immune system. The
export of these hundreds of proteins is complicated by the fact that the malaria parasite conceals itself inside a
parasitophorous vacuole (PV) derived from invagination of the host cell plasma membrane during invasion.
Following secretion into the PV, proteins destined for export must be unfolded and transported across the PV
membrane (PVM) into the host cell in an ATP-dependent process. The export pathway is essential for parasite
survival, making members of the pathway attractive potential drug targets. The complexity and breadth of its
host-cell remodeling machinery make P. falciparum a rich and exciting system for the study of host-pathogen
interactions. However, many of the molecular mechanisms underlying this parasite's ability to hijack human red
blood cells remain enigmatic, as much of the P. falciparum proteome has proven recalcitrant to structural and
biochemical characterization using traditional recombinant approaches. The goal of the proposed work is to
leverage and build upon the latest advances in single-particle cryo electron microscopy and cryo focused ion
beam-enabled in situ cryo electron tomography to elucidate the molecular mechanisms underlying effector
protein export in P. falciparum and to identify promising targets for structure-based design of new anti-malarial
therapeutics. Three aims are proposed to accomplish these goals: 1) Establish an in vitro translocation activity
assay for the Plasmodium Translocon of Exported Proteins (PTEX), a novel and essential membrane protein
complex, through which all exported effector proteins must pass in order to reach the host cell cytosol. The
established assay will enable biochemical characterization of the molecular mechanism of protein translocation
and screening of inhibitors obtained via structure-guided design of PTEX inhibitors. 2) Structure determination
of novel protein complexes of the P. falciparum exportome. 3) Direct visualization of the supramolecular effector
protein export machinery in situ at the host-pathogen interface in P. falciparum-infected erythrocytes. The
pr...

## Key facts

- **NIH application ID:** 10479868
- **Project number:** 5DP5OD029613-03
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Chi-Min Ho
- **Activity code:** DP5 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $405,000
- **Award type:** 5
- **Project period:** 2020-09-10 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10479868

## Citation

> US National Institutes of Health, RePORTER application 10479868, Molecular basis of effector protein export in the malaria parasite Plasmodium falciparum (5DP5OD029613-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10479868. Licensed CC0.

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